新冠疫情期間聞“熱”喪膽，有你嗎？——發(fā)熱的病因和機制

我們可以在發(fā)熱的哪些環(huán)節(jié)實施解熱呢?Whichstepoffevercanwecarryoutantipyretictreatmentstodecreasebodytemperature?0102?發(fā)熱是機體的敵人還是朋友?Isfeveranenemyorafriendtoourbody?發(fā)熱的機制RegulatorymechanismsinvolvedinthepathogenesisoffeverPyrogenicactivator11發(fā)熱激活物Releaseofcentralmediators（PGE2,cAMP,Na+/Ga2+↑,AVP,

CRH,etc.）ThermoregulationcenterSet-point↑CutaneousvasoconstrictionHeat

dissipation↓Bodytemperature↑Heatproduction↑

34ThermoregulationeffectorresponseSkeletalmuscletension釋放中樞調(diào)節(jié)介質(zhì)骨骼肌緊張體溫中樞調(diào)定點上移皮膚血管收縮調(diào)溫效應器反應產(chǎn)熱增多體溫升高散熱減少Activationofmonocytes/macrophagesReleaseofEPs(IL-1,IL-6,TNF)2激活單核細胞或巨噬細胞釋放內(nèi)生致熱原發(fā)熱激活物是指能激活人體產(chǎn)內(nèi)生致熱原細胞產(chǎn)生內(nèi)生致熱原的一類物質(zhì)。Thesubstanceswhichcanactivateendogenouspyrogens(EP)-producingcellsofthehumanbodytoproduceendogenouspyrogens(EP)aretermedpyrogenicactivators.一、發(fā)熱激活物PyrogenicactivatorInfectivefactors一、發(fā)熱激活物——外生致熱原Pyrogenicactivator—Exogenouspyrogens大腸桿菌(Escherichiacoli)肺炎雙球菌(Streptococcuspneumoniae)G-：脂多糖(LPS)內(nèi)毒素(endotoxin，ET)G+：外毒素(exotoxin)

肽聚糖(peptidoglycan)01白假絲酵母菌(Candidaalbicans)血吸蟲(Schistosome)03Exogenouspyrogens流感病毒(Influenzavirus)新冠病毒(COVID-19)02細菌Bacteria病毒Virus真菌、螺旋體、寄生蟲Fungi,Spirochetes,Parasitenon-microbialpyreticsubstances01抗原抗體復合物Antigen-antibodycomplexes系統(tǒng)性紅斑狼瘡(Systemiclupuserythematosus)類風濕(Rheumatoid)一、發(fā)熱激活物——非微生物致熱物質(zhì)Pyrogenicactivator—non-microbialpyreticsubstances02嚴重組織損傷Severetissuedamages急性心肌梗死，外傷，重大外科手術(shù)Acutemyocardialinfarction,trauma,majorsurgicaloperationsNon-infectivefactors0304類固醇Steroids尿酸鹽結(jié)晶UratecrystalsPyrogenicactivator1發(fā)熱激活物Activationofmonocytes/macrophages2ReleaseofEPs激活單核細胞或巨噬細胞釋放內(nèi)生致熱原二、內(nèi)生致熱原endogenouspyrogen,EP內(nèi)生致熱源是在發(fā)熱激活物的作用下，由產(chǎn)EP細胞產(chǎn)生的可以直接引起發(fā)熱的物質(zhì)。Epscanbedefinedasanymoleculeswithdirectfever-inducingactivities,whichareproducedendogenouslybyEP-producingcellsuponstimulationbyexogenouspyrogensorendogenouspyrogenicactivators.單核細胞(Monocytes)巨噬細胞(Macrophages)枯否細胞(Kupffercells)淋巴細胞(lymphocytes)神經(jīng)膠質(zhì)細胞(Neuroglialcells)腫瘤細胞(Tumorcells)白細胞介素-1(IL-1)腫瘤壞死因子(TNF)干擾素(IFN)白細胞介素-6(IL-6)巨噬細胞炎癥蛋白-1(MIP-1)產(chǎn)EP細胞EP種類二、內(nèi)生致熱原endogenouspyrogen，EP發(fā)熱不是絕對的壞事

Feverisnotabsolutelybad增強機體抗感染能力Enhancetheanti-infectioncapacity引起急性期反應Triggeracutephaseresponse分解代謝旺盛Acceleratetherateofcatabolism引發(fā)器官功能紊亂Triggerdysfunctionoforgans導致胎兒發(fā)育障礙、脫水和高熱驚厥Causesfetaldevelopmentaldisorders,dehydration,febrileseizures藥物降溫Drugcooling

物理降溫Physicalcooling38℃發(fā)熱的機制RegulatorymechanismsinvolvedinthepathogenesisoffeverPyrogenicactivator11發(fā)熱激活物Releaseofcentralmediators（PGE2,cAMP,Na+/Ga2+↑,AVP,

CRH,etc.）ThermoregulationcenterSet-point↑CutaneousvasoconstrictionHeat

dissipation↓Bodytemperature↑Heatproduction↑

34ThermoregulationeffectorresponseSkeletalmuscletension釋放中樞調(diào)節(jié)介質(zhì)骨骼肌緊張體溫中樞調(diào)定點上移皮膚血管收縮調(diào)溫效應器反應產(chǎn)熱增多體溫升高散熱減少Activationofmonocytes/macrophagesReleaseofEPs(IL-1,IL-6,TNF)2激活單核細胞或巨噬細胞釋放內(nèi)生致熱原三、EP進入體溫調(diào)節(jié)中樞的方式TheroutesforEPsignalsintothethermoregulatorycenter脈絡叢(Choroid

plexus)直接通過血腦屏障Directtransportedacrossblood-brainbarrier(BBB)通過迷走神經(jīng)傳入纖維Viastimulationofvagusnerve通過下丘腦終板血管器Viaorganumvasculosumlaminaeterminalis(OVLT)下丘腦終板血管器(OVLT)視交叉(Opticchiasma)毛細血管capillary（1）通過下丘腦終板血管器Viaorganumvasculosumlaminaeterminalis(OVLT)OVLT神經(jīng)元

OVLTneurons介質(zhì)mediatorsPOAH神經(jīng)元POAH

neuronsEPOpticchiasma3rdventricleSuperioropticrecess下丘腦終板血管器(OVLT)視交叉(Opticchiasma)第三腦室視上隱窩視交叉介質(zhì)mediatorsPOAH神經(jīng)元POAH

neurons（2）直接通過血腦屏障Directtransportedacrossblood-brainbarrier(BBB)01

血腦屏障的毛細血管床部位存在IL-1,IL-6,TNF的

可飽和轉(zhuǎn)運機制。ThecapillaryendothelialcellsatBBBpossessseveralundefinedtransportersforIL-1,IL-6,andTNF.BBBBloodBrainIL-1、IL-6、TNF（2）直接通過血腦屏障Directtransportedacrossblood-brainbarrier(BBB)02通過脈絡叢被動擴散轉(zhuǎn)運入腦，通過腦脊液到達POAH。EPsmayenterintothebrainbypassivediffusionacrossthechoroidplexus,reachingPOAHthroughcerebrospinalfluidcirculation.脈絡叢(choroid

plexus)內(nèi)生致熱原可刺激胸、腹腔臟器巨噬細胞周圍的迷走神經(jīng)，通過迷走神經(jīng)傳入纖維將致熱信號傳入體溫調(diào)節(jié)中樞。EPscanstimulatethevagusnervearoundhepaticmacrophages,andsendtheperipheralpyrogenicsignalintothethermoregulatorycenterthroughtheafferentfibersofthevagusnerve.（3）通過迷走神經(jīng)傳入纖維ViastimulationofvagusnerveHeartBronchioflungsLiverStomachSmallintestinesLargeintestineRectum體溫調(diào)定點上移ThermoregulationcenterSet-point↑？EPs內(nèi)生致熱源能直接引起調(diào)定點上移？CanEPsdirectlyelevatethetemperatureset-point?發(fā)熱的機制RegulatorymechanismsinvolvedinthepathogenesisoffeverPyrogenicactivator11發(fā)熱激活物ThermoregulationcenterSet-point↑Releaseofcentralmediators3釋放中樞調(diào)節(jié)介質(zhì)體溫中樞調(diào)定點上移Activationofmonocytes/macrophagesReleaseofEPs(IL-1,IL-6,TNF)2激活單核細胞或巨噬細胞釋放內(nèi)生致熱原四、中樞發(fā)熱介質(zhì)CentralmediatorsoffeverCentralmediatorsoffeverPositiveNegativePGE2AVPCRHα-MSHcAMPlipocortin-1Na+/Ga2+ratioIL-10NO熱限Febrileceiling發(fā)熱時體溫上升的高度被限制在一定范圍內(nèi)的現(xiàn)象稱為熱限。Thephenomenonthattheelevationofbodytemperatureislimitedtoacertainrangeisfebrileceiling.熱限Febrileceiling體溫升高Bodytemperature↑EP體溫正調(diào)節(jié)中樞Positivethermoregulatorycenter體溫負調(diào)節(jié)中樞Negativethermoregulatorycenter負調(diào)節(jié)介質(zhì)Negativemediators42℃41℃Pyrogenicactivator11發(fā)熱激活物Releaseofcentralmediators（PGE2,cAMP,Na+/Ga2+↑,AVP,

CRH,etc.）ThermoregulationcenterSet-point↑CutaneousvasoconstrictionHeat

dissipation↓Bodytemperature↑Heatproduction↑

34Thermoregula